Mass spectrometry of solution and apparatus

ABSTRACT

A mass spectrometric apparatus includes a device for supplying a sample solution to an outlet, the sample solution including a solvent and a solute, a first ionization device for receiving the sample solution from the outlet and electrospraying the received sample solution, thereby ionizing at least a portion of the received sample solution, a second ionization device for receiving at least a portion of the electrosprayed sample solution produced by the first ionization device and ionizing at least a portion of the received electrospayed sample solution, thereby producing ions, and a mass spectrometric device for receiving at least some of the ions produced by the second ionization device and analyzing masses of the received ions.

This application is a continuation application of Ser. No. 08/562,369,filed Nov. 22, 1995, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to mass spectrometry of a solution, andparticularly to a mass spectrometer for analyzing substances in asolution and an apparatus for combining a liquid chromatograph used forseparation and analysis of a mixed sample and the mass spectrometer.

At present, development of mass spectrometry of biological substances isregarded as important in the field of analysis. Biological substancesare generally dissolved in a solution as a mixture, so that an apparatusfor combining a means for separating a mixture and a mass spectrometeris under development. As a typical apparatus of this method, there is aliquid chromatograph--mass spectrometer (hereinafter abbreviated toLC/MS) available. A liquid chromatograph (hereinafter abbreviated to LC)is superior in separation of a mixture but cannot identify eachsubstance, whereas a mass spectrometer (hereinafter abbreviated to MS)is highly sensitive and superior in identification ability but notsuitable to analysis of a mixture. Therefore, an LC/MS using an MS as anLC detector is very useful in analysis of a mixture.

The LC/MS using the conventional atmospheric pressure chemicalionization method which is disclosed in Japanese Patent ApplicationLaid-Open 5-325882 will be explained hereunder by referring to FIG. 9.

A sample solution eluted from a liquid chromatograph 14 is introducedinto a metallic tube 3 via a pipe 1 and a connector 2. The samplesolution comprises a sample and a mobile phase (a buffer solution whichflows into the separation column when the sample is separated in theLC). However, for the purpose of improving the ionization efficiency inthe ion source (according to the present invention, the term "ionsource" it means a portion for converting a substance to be analyzedexisting in the liquid phase to ions in the gas phase and includes aspray portion for spraying a solution, a vaporization portion forvaporizing droplets generated by the spray portion, and an ionizationportion for ionizing a substance), a solvent different from the mobilephase may be added. The metallic tube 3 is embedded in a metallic block4a. When the metallic block 4a is heated by a heating means such as aheater, a sample solution introduced in the metallic tube 3 is sprayed.Fine droplets generated by spraying are introduced into and vaporized inthe vaporization portion 5 comprising heated metallic block 4b. Samplemolecules vaporized in the vaporization portion 5 are introduced intothe ionization portion 6. A needle electrode 7 is installed in theionization portion 6. When a high voltage is applied to this needleelectrode 7 from a high voltage source 8a, a corona discharge isgenerated in the ionization portion 6.

Assuming A to be sample molecules to be analyzed and B to be moleculesof a reaction gas, the atmospheric pressure chemical ionization methodis a method for ionizing A by a chemical reaction of A and B. As atypical ion chemical reaction, there are a protonation reaction and adeprotonation reaction available as shown below.

    A+BH.sup.+ →AH++B (Protonation reaction)

    A+B.sup.- →(A-H).sup.- +BH (Deprotonation reaction)

According to the prior art shown in FIG. 9, hydronium ions (H₃ O⁺) aregenerated when a corona discharge is generated in the atmosphere andions AH+ of the sample A are generated by using the following reactionbetween the hydronium ions and the sample molecules A.

    A+H.sub.3 O.sup.+ →AH.sup.+ +H.sub.2 O

Ions of the sample generated by chemical ionization in the ionizationportion 6 have their trajectory deflected by a voltage applied to adeflection electrode 31 by a power source 30 and drift toward an ionintroduction aperture 9a. The ions pass by the ion introduction aperture9a and are introduced into a high vacuum portion 12 which is exhaustedto a high vacuum by an exhaust system 10b via a differential pumpingportion 11 which is evacuated by an exhaust system 10a and an ionintroduction aperture 9b. When ions and solvent molecules pass throughthe ion introduction apertures 9a and 9b, they are cooled by adiabaticexpansion, so that so-called clustering for condensing the ions andsolvent molecules again occurs. To prevent the clustering, electrodes inwhich the ion introduction apertures 9a and 9b are formed are heated.The mass of ions introduced into the high vacuum portion 12 is analyzedby a mass spectrometric portion 13. Nonvolatile compounds that are notionized in the ionization portion 6 are diffused in the atmosphere andcaptured by a capture plate 32.

An LC/MS using the conventional electrospray method which is disclosedin Japanese Patent Application Laid-Open 6-102246 will be explained byreferring to FIG. 10. A sample solution eluted from the LC is introducedinto the metallic tube 3 via the pipe 1 and the connector 2. A highvoltage is applied between the metallic tube 3 and an electrode 21c inwhich the ion introduction aperture 9a is formed by using a high voltagesource 8b and the sample solution is electrostatically sprayed. Toassist electrospray, gas such as nitrogen gas is let flow from a spraygas outlet 40. When fine charged droplets generated by electrospray arevaporized, gaseous ions are generated. However, the diameter of dropletsat the center of the jet is large and it is difficult to vaporizedroplets with a large diameter, and furthermore when droplets with alarge diameter adhere to the electrode 21c, the temperature of theelectrode 21c drops and the ion intensity obtained in the massspectrometric portion may vary. Therefore, a shielding plate 41 forshielding the center of the jet is installed between the metallic tube 3and the electrode 21c and the outer periphery of the jet is sprayedtoward the ion introduction aperture 9a. Generated ions are introducedinto the high vacuum portion 12 via the ion introduction aperture 9a,the differential pumping portion 11, and the ion introduction aperture9b and analyzed by the mass spectrometric portion installed in the highvacuum portion 12.

For analysis of biological substances and environmental contaminants, amethod for analyzing a sample solution containing nonvolatile compoundsof high concentration is required.

For example, in the LC, the mobile phase including a nonvolatile salt isoften used experientially so as to enhance the separation ability andthe reproducibility of the retention time. As a result, a method foranalyzing a sample solution containing a nonvolatile salt is desirablefor a detector of the LC.

Nonvolatile compounds are contained not only in samples obtained from aliving organism such as urine, perspiration, and blood, but also insamples relating to the environment such as effluents from a factory andwater of a lake or marsh. To remove nonvolatile compounds from thesesamples, a complicated pretreatment such as desalting is required.Therefore, in order to analyze biological substances and environmentalcontaminants quickly, a method for analyzing a sample solutioncontaining nonvolatile compounds is required.

However, in a mass spectrometric apparatus using the conventionalatmospheric pressure chemical ionization method shown in FIG. 9, when asample solution containing nonvolatile compounds of high concentrationis introduced into the ion source of the mass spectrometric apparatuscomprising an ion source, a differential pumping portion, and a massspectrometric portion, a problem arises that ions of a substance to beanalyzed cannot be analyzed stably for many hours. The reason is thatsince the sample solution is sprayed by using the heated metallic tube,solvent molecules are vaporized in the tube and nonvolatile compoundsare salted out on the inner wall of the tube. The inner diameter of themetallic tube becomes smaller because nonvolatile compounds are saltedout on the tube wall, and the metallic tube finally clogs up. Therefore,the spray status varies with time, so that the ion generation in theionization portion is adversely affected.

When fine droplets containing nonvolatile compounds adhere to theneighborhood of the ion introduction aperture installed between the ionsource and the differential pumping portion, solvent molecules arevaporized and nonvolatile compounds are salted out around the aperture.In the conventional apparatus shown in FIG. 9, by installing the captureplate on the ion source side, a method for salting out nonvolatilecompounds contained in droplets adhered to the capture plate on thecapture plate is used so as to reduce salting out of nonvolatilecompounds around the aperture. However, it is actually difficult tocapture all droplets sprayed in the atmosphere on the capture plate andsome of the droplets are diffused in the atmosphere and reach theaperture. Therefore, if the analysis is continued for many hours, anactual problem arises that salted nonvolatile compounds clog up theaperture and ions cannot be introduced into the mass spectrometricportion.

As an example of a sample solution containing nonvolatile compounds, acase where a sodium phosphate water solution (hereinafter described as aphosphoric acid buffer) having a concentration of 20 millimoles/liter isintroduced into the ion source at a flow rate of 50 microliters perminute will be described. A phosphoric acid buffer is a mobile phasewhich is often used in a detector other than the MS, for example, in anLC having an ultraviolet absorption detector. When a conventional LC/MSuses a phosphoric acid buffer, the observed ion intensity startsdropping within about 30 minutes after the start of analysis and dropsdown to about 1/10 of the initial value after one hour has elapsed, andthe continuation of analysis becomes difficult.

Whether a problem that the metallic tube or aperture clogs up due tosalting out of nonvolatile substances arises or not depends on the kindof nonvolatile substances and the total amount of nonvolatile substances(namely, the concentration of nonvolatile substances and the flow rateof the sample solution) introduced into the ion source. For example,when substances are analyzed at a flow rate of 1 microliter per minutecontinuously for several hours using a phosphoric acid buffer having aconcentration of 10 millimoles/liter, the ion intensity observed by themass spectrometer may decrease.

Even in the apparatus using the conventional electrospray method shownin FIG. 10, the outer periphery of a jet is sprayed toward the ionintroduction aperture, so that some of the droplets generated by thespray reach in the neighborhood of the ion introduction aperture.Therefore, when a sample solution containing nonvolatile compounds ofhigh concentration is introduced into the ion source, there is apossibility that the ion introduction aperture may clog up withnonvolatile compounds salted out by vaporization of droplets. Therefore,in the same way as with an apparatus using the atmospheric pressurechemical ionization method shown in FIG. 9, a problem arises that if theanalysis is continued for many hours, the aperture clogs up and ionscannot be introduced into the mass spectrometric portion.

For the aforementioned reason, an apparatus having an ion sourceallowing stable analysis for many hours even if a solution containingnonvolatile compounds of high concentration is introduced is required.

SUMMARY OF THE INVENTION

An object of the present invention is to prevent a metallic tube and anion introduction aperture from clogging up by salting out of nonvolatilecompounds. Another object of the present invention is to allow analysisby an LC/MS using a mobile phase containing a nonvolatile salt whichcannot be used for many hours conventionally.

According to the present invention, the above objects are accomplishedby introducing a sample solution containing nonvolatile compounds sentto the ion source into the metallic tube, spraying the sample solutionby electrospray at a high voltage applied between the metallic tube andthe electrode externally installed, ionizing gaseous sample moleculesobtained by vaporizing obtained droplets by chemical reaction, andanalyzing ions of sample molecules by the MS.

Namely, the present invention is characterized in the method andconstitution that nonvolatile compounds contained in a sample solutionare ionized by the first ionization means and removed by the electricfield, and then a substance contained in the sample solution to beanalyzed is ionized by the second ionization means, and ions of thetarget substance are analyzed by the spectrometric portion.

Since a sample solution sent to the ion source is sprayed byelectrospray, no nonvolatile compounds will be salted out byvaporization of solvent molecules and the metallic tube can be preventedfrom clogging.

Electrospray is a method for collecting ions in a solution on the liquidsurface by the electric field and crushing the solution by the force ofrepulsion acting between ions so as to generate fine charged droplets.When charged droplets obtained by electrospray are vaporized, ionsexisting in the solution can be fetched in the gas phase. Therefore,some of nonvolatile compounds which exist in the solution as ions can beconverted to gaseous ions by electrospray. Ions generated byelectrospray are drifted by the electric field between the metallic tubeand the metallic block constituting the vaporization portion andcaptured by the metallic block or the trajectory thereof is curved bythe potential applied to the needle electrode installed in theionization portion, so that they cannot reach the ion introductionaperture. Therefore, no nonvolatile compounds will salt out around theion introduction aperture and the aperture will not be clogged out.

A substance to be analyzed which is not ionized in the solution is notconverted to gaseous ions by electrospray but diffused in the atmosphereas gaseous molecules which are electrically neutral and reaches theionization portion. In the ionization portion, ions of the substance tobe analyzed are generated by a corona discharge generated by the needleelectrode and chemical ionization reaction caused by it. Ions of thesubstance to be analyzed are fetched and analyzed by the massspectrometric portion in a vacuum via the ion introduction aperture.

A nonvolatile salt which is represented by sodium phosphate isdissociated in a solvent such as water and exists as ions. Therefore,the LC/MS of the present invention can use a mobile phase containing anonvolatile salt which is represented by a phosphoric acid buffer thoughit is conventionally difficult to use for many hours.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view showing the constitution of a massspectrometric apparatus using an electrospray method as a firstionization means and a chemical ionization method as a second ionizationmeans which is an embodiment of the present invention;

FIG. 2 is an illustration for explaining the embodiment shown in FIG. 1in detail;

FIG. 3 is a schematic sectional view showing an embodiment in which theend of the metallic tube is placed in the volatilization portion and asample solution is directly sprayed toward the metallic block;

FIG. 4 is a schematic sectional view showing an embodiment in which ashielding plate for preventing large droplets from splashing andreaching the ionization portion is installed;

FIG. 5 is a schematic sectional view showing an embodiment in whichirradiation of infrared light is used as a vaporization method of thevaporization portion;

FIG. 6 is a schematic sectional view showing an embodiment in which asample solution is sprayed perpendicularly to the center axis of the ionintroduction aperture;

FIG. 7 is a schematic sectional view showing an embodiment in which apan for collecting droplets is used;

FIG. 8 is a schematic sectional view showing an embodiment in which agas spray ionization method is used as a first ionization means;

FIG. 9 is a schematic view showing the constitution of a liquidchromatograph--mass spectrometer using the conventional atmosphericpressure chemical ionization method;

FIG. 10 is a schematic sectional view showing the constitution of aliquid chromatograph--mass spectrometer using the conventionalelectrospray method;

FIG. 11 is a graph showing a change with time of the ion intensityobtained by a mass spectrometer using the conventional atmosphericpressure chemical ionization method; and

FIG. 12 is a graph showing a change with time of the ion intensityobtained by the mass spectrometer of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 is a schematic view showing the constitution of the massspectrometric apparatus of the present invention. A sample separated bya liquid chromatograph 14 is sprayed by an electrospray portion 15together with the mobile phase. The sample and the mobile phaseconstitute a sample solution including a solvent and a solute. Dropletsobtained by spray are promoted in vaporization in a vaporization portion5. Gaseous sample molecules generated by the ionization portion 5 areionized by chemical reaction in an ionization portion 6. Ions of thesample generated by the ionization portion 6 are introduced into an ionintroduction aperture 9b and a high vacuum portion 12 which is exhaustedby an exhaust system 10b via an ion introduction aperture 9a and adifferential pumping portion 11 which is exhausted by an exhaust system10a.

Ions introduced into a vacuum are analyzed in mass by a massspectrometric portion 13. The ionization portion 6 may be installed inthe differential pumping portion 11. The differential pumping portion 11has a pressure between several Pascal to several hundreds Pascal and cangenerate ions by chemical reaction because sample molecules and reactiongas collide with each other. FIG. 2 is a drawing showing a more detailedstructure than the constitution shown in FIG. 1. The liquidchromatograph 14 comprises a mobile phase reservoir 50, a pump 51, asample introduction portion 52, a separation column 53, and a pipe 1. Amobile phase in the mobile phase reservoir 50 is pumped up by the pump51 and sent to the sample introduction portion 52 and the separationcolumn 53 at the predetermined flow rate via the pipe 1. The sample isintroduced from the sample introduction portion 52 and sent to theseparation column 53 together with the mobile phase. The separationcolumn 53 is filled up with a packing material. The sample is separatedby interaction with the packing material. The sample solution elutedfrom the separation column 53 is introduced into the metallic tube 3 viathe pipe 1 and the connector 2. When a high voltage is applied betweenthe metallic tube 3 and the metallic block 4b by using a high voltagesource 8b, charges with the same sign are accumulated on the surface ofthe solution by the electric field in the neighborhood of the end of themetallic tube 3. When the electrostatic repulsion force generated by theaccumulated charges becomes stronger than the surface tension of thesolution, so-called electrospray for generating many fine chargeddroplets is caused. Fine droplets generated by spray are introduced intothe vaporization portion 5 comprising the heated metallic block 4b. Themetallic block 4b is heated at about 300° C. by a heater (not shown inthe drawing). Droplets generated by spray are vaporized by heat whilethey are passing through the aperture of the metallic block 4b.

Sample molecules vaporized in the vaporization portion 5 are introducedinto the ionization portion 6. The needle electrode 7 is installed inthe ionization portion 6. When a high voltage is applied to this needleelectrode 7 by using the high voltage source 8a, a corona discharge isgenerated in the ionization portion 6. When gaseous sample moleculesobtained by volatilization of droplets reach the corona dischargeportion, a chemical reaction with primary ions such as hydronium ionsgenerated by the corona discharge is caused and ionization of samplemolecules is realized.

In this case, since the sample solution is sprayed by electrospray,nonvolatile compounds will not be salted out by vaporization of solventmolecules and the metallic tube 3 can be prevented from clogging up. Thepart of the nonvolatile compounds in the solution which is ionized isconverted to gaseous ions by electrospray. These ions are captured bythe metallic block 4b constituting the vaporization portion 5 or thetrajectory thereof is curved by the potential applied to the needleelectrode 7 installed in the ionization portion 6, so that they cannotreach the ion introduction aperture 9a. Therefore, even if a samplesolution containing nonvolatile compounds is used, the nonvolatilecompounds will not salt out around the ion introduction aperture 9a andthere is no possibility that the ion introduction aperture 9a is cloggedup.

Therefore, according to the present invention, even if a sample solutioncontaining nonvolatile compounds of high concentration is introduced, anion source for generating ions of a substance to be analyzed stably formany hours can be realized. Furthermore, according to the presentinvention, a mass spectrometric apparatus for analyzing a samplesolution containing nonvolatile compounds of high concentration stablyfor many hours can be realized.

The polarity (positive or negative) of voltages to be applied to theneedle electrode 7 and the metallic tube 3 by the high voltage sources8a and 8b may be switched independently of each other according to theproperty of a substance to be analyzed and the property of nonvolatilecompounds in the sample solution. For example, when a substance to beanalyzed has a strong proton affinity and is apt to be converted toprotonated ions, it is desirable to apply a positive voltage to theneedle electrode 7. When a substance to be analyzed has a property thatnegative ions which are deprotonated are easily generated, it isdesirable to apply a negative voltage to the needle electrode 7.

Next, the effect of the present invention described in FIG. 2 will beexplained on the basis of the experimental results. A 50% methanol watersolution containing sodium dihydrogenphosphate having a concentration of20 millimol/liter is used as a mobile phase and fed to the ion source byan LC pump at a flow rate of 50 micro liter per minute.β-hydroxytheophylline (concentration 100 ppm) is used as a sample. Thissample is introduced from an LC sample injector in units of 2 microliters each time by taking time. The mass spectrometer monitorsprotonated molecular ions (molecular weight 225) ofβ-hydroxytheophylline.

FIG. 11 shows a change with time of the ion intensity observed by anapparatus using the conventional atmospheric pressure chemicalionization method. The ion intensity starts reduction about 30 minutesafter start of analysis. When the apparatus is disassembled andexamined, it is found that the cause of reduction of the ion intensityis that a nonvolatile salt (sodium phosphate) in the mobile phase saltsout in the neighborhood of the ion introduction aperture and the ionintroduction aperture is clogged up.

FIG. 12 shows a change with time of the ion intensity measured by usingthe apparatus of the present invention shown in FIG. 2. The dotted lineshown in the drawing indicates the mean level of the maximum values ofthe ion intensity when each sample is introduced and almost the sameintensity is obtained over a period of 6 hours. As shown in FIG. 12,according to the present invention, even if a mobile phase containing anonvolatile salt is introduced into the ion source, a reduction in theion intensity caused by clogging of the metallic tube or ionintroduction aperture is not seen and ions are observed stably for manyhours.

As shown in FIG. 11, if a mobile phase containing a nonvolatile salt isused in the conventional LC/MS under the aforementioned condition, acleaning operation for the aperture and others is required everyanalysis for about 30 minutes. To clean the aperture, it is necessary tostop the exhaust system and disassemble the apparatus. To restartanalysis, it requires about 2 hours including the time of reexhaustafter completion of cleaning, so that the operability as an analyticalapparatus is extremely bad. Furthermore, when the vacuum pump startsexhausting from the atmospheric pressure to a vacuum, it is applied witha great load, so that repetition of stopping and reexhausting theexhaust system is a factor for shortening the life time of the vacuumpump. Furthermore, when the apparatus is disassembled and assembledagain, the analytical conditions are changed by a shift in installationposition of each part constituting the ion source and a change intemperature of the heating part, and the reproducibility of the ionintensity observed by the mass spectrometer is bad, and the accuracy ofquantitative analysis of a substance to be analyzed gets worse. In theconventional apparatus, it is necessary to end one analysis includingadjustment of the ion source for 30 minutes during which ions areobserved stably. However, a time of 30 minutes is not always sufficientfor use of the separation ability of the LC at its maximum. For example,there is a method available for changing the composition of a mobilephase with time and eluting a substance to be analyzed. However, if thecomposition is changed in a short time, no sufficient separation may beobtained. The cause thereof is considered to be that if the compositionof the mobile phase is changed too fast, the packing material in theseparation column and the mobile phase cannot be kept in the equilibriumstate.

The apparatus of the present invention can be used continuously forabout 10 hours even if a mobile phase containing a nonvolatile saltwhich is conventionally difficult to use is used. If an operator cleansand adjusts the apparatus before starting operation every morning, hecan obtain data during his operation in a day. Therefore, the apparatusof the present invention has advantages that the operability isremarkably improved compared with a conventional apparatus, and theburden imposed on the vacuum pump is lightened, and the life time of thevacuum pump can be lengthened. The apparatus of the present invention ischaracterized in that since it can repeat measurement under the sameanalytical condition, the accuracy of quantitative analysis is high anda sufficient time can be put in separation, so that analysis by theLC/MS fully utilizing the separation ability of the LC is possible.

Whether a problem that ions cannot be observed stably due to clogging ofthe metallic tube or aperture arises or not depends on the kind ofnonvolatile substances and the total amount (namely, the concentrationof nonvolatile substances and the flow rate of the solution) sent to theion source.

For example, there is a capillary electrophorsis method (hereinafterabbreviated to CE) available as a separation means different from theLC. This is a method for separating a sample by electrophorsis using afused-silica capillary of several tens microns in inner diameter. Abuffer solution containing a nonvolatile salt having a concentration ofseveral tens millimol/liter may be used as a separation medium of CE. Aflow of a buffer solution which is called an electroosmosis flow isgenerated due to dissociation of the inner wall of the capillary, thoughthe rate of electroosmosis flow is generally low such as 0.1 micro literper minute or less. Therefore, in a so-called CE/MS using an MS as a CEdetector, a problem of clogging of the aperture will not arise.

When the flow rate of a solution sent from the LC is high and it isdifficult to continue electrospray stably, as shown in FIG. 2, asplitter 16 may be installed so as to introduce a part of the solutioninto the metallic tube 3. Also as shown in FIG. 2, a spray gas 17 mayflow from the outside of the metallic tube 3 so as to assist theelectrospray.

When a narrow separation column with an inner diameter of from severaltens microns to several hundreds microns which is called a capillarycolumn is used in the LC, it may be difficult to continue theelectrospray stably because the flow rate of a solution sent from the LCis low. It may be also difficult to continue the electrospray stablybecause the viscosity or electric conductivity of the solution isexcessively high depending on the concentration of the solute. If thisoccurs, also shown in FIG. 2, it is possible to provide an area forflowing an auxiliary spray solution 18 around the metallic tube 3 andmix it with a solution sent from the LC in the neighborhood of the endof the metallic tube 3 so as to set the flow rate, viscosity, andelectric conductivity to the conditions for continuing the electrospraystably.

As shown in FIG. 3, the end of the metallic tube 3 may be placed in thevolatilization portion 6. Also as shown in FIG. 3, a solution may besprayed directly toward the metallic block 4b. A sample solution issubjected to first ionization, that is, electrospray at a high voltageapplied between the metallic tube 3 and the metallic block 4b by thehigh voltage source 8b. The metallic tube 3 and the metallic block 4bare insulated from each other by an insulating tube 19. Droplets sprayedto the metallic block 4b which is heated to a temperature higher thanthe boiling point of the solution are vaporized instantaneously andgaseous sample molecules are obtained. When sample molecules reach thecorona discharge portion, they are chemically reacted with primary ionssuch as hydronium ions generated by corona discharge and ionization ofsample molecules is realized by second ionization, that is, chemicalionization. Ions of sample molecules are fetched by the high vacuumportion 12 which is exhausted to about 10-3 Pa by the exhaust system 10bvia the differential pumping portion 11 which is exhausted to fromseveral tens Pa to several hundreds Pa by the ion introduction aperture9a and the exhaust system 10a and the mass thereof is analyzed by themass spectrometric portion 13.

To increase the arrival efficiency of sample molecules to the ionizationportion, as shown in FIG. 3, it is possible to provide an inclined wallinside the metallic block 4b, electrostatically spray sample moleculestoward the inclined wall in the oblique direction, and flow a gas 20such as nitrogen gas toward the ionization portion. It is desirable topreheat the gas 20 at a temperature higher than the room temperature.

When large droplets are generated by electrospray in an apparatus havingthe constitution shown in FIG. 2, they cannot be vaporized perfectly inthe vaporization portion 5 by the heated metallic block 4b and may reachthe ionization portion 6 where a corona discharge is generated by theneedle electrode 7 as they are. When droplets reach the portion where acorona is generated, there is a possibility that they short-circuit theneedle electrode 7 and the ion introduction aperture 9a and the highvoltage source 8a or others may be damaged.

To prevent it, as shown in FIG. 4, it is possible to arrange anelectrode 21a so as to shield the ionization portion 6 where a coronadischarge is generated by the end of the metallic tube 3 and the needleelectrode 7 and electrostatically spray droplets toward the electrode21a. In this case, to increase the vaporization efficiency of droplets,it is desirable to heat the electrode 21a by a heater 22a beforehand. Inan apparatus having the constitution shown in FIG. 4, gaseous moleculesare transported and ionized in the ionization portion 6, so that ashort-circuit due to droplets adhered to the needle electrode 7 can beavoided. In FIG. 41 the shape of the electrode 21a may be not onlylaminar but also meshed. To increase the arrival efficiency of samplemolecules to the ionization portion 6, it is possible to flow a gas 20toward the ionization portion 6 as shown in FIG. 3.

In the embodiments shown in FIGS. 2 to 4, a constitution in which aheated metallic block is used as a means for vaporizing droplets isshown. However, a method for irradiating infrared light may be used forvaporization of droplets.

FIG. 5 shows an embodiment using irradiation of infrared light as avaporization means. A sample solution is electrostatically sprayed at avoltage applied between the metallic tube 3 and a mesh 23a. It isdesirable that the mesh 23a is heated beforehand. Droplets obtained byspray are sent to the vaporization portion 5. Infrared light emittedfrom a heater 22b connected to a power source 24 is irradiated todroplets in the vaporization portion 5 so as to vaporize them. When theheater 22b is degraded because droplets collide directly with it, it ispossible to install a glass tube 25 inside the heater 22b so as toprotect it. To increase the vaporization efficiency of droplets, it isdesirable to remove water vapor in the spray gas 17 beforehand. It isalso desirable to heat the spray gas 17 at the room temperature orhigher beforehand. Gaseous sample molecules obtained in the vaporizationportion 5 are ionized in the ionization portion 6.

In an apparatus having the constitution shown in FIGS. 2 to 5, a samplesolution containing nonvolatile compounds can be used in the LC/MS.However, when a sample solution containing nonvolatile compounds of anextremely high concentration is introduced into the ion source or theanalysis requires more hours, it is possible to change the spraydirection of the sample solution to a direction different from thearrangement direction of the ion introduction aperture. FIG. 6 shows anexample in which a sample solution is sprayed perpendicularly to thecenter axis of the ion introduction aperture 9a. The sample solutionintroduced into the metallic tube 3 is sprayed toward an oppositeelectrode 21b. It is desirable that the electrode 21b is heated at atemperature higher than the boiling point of the solution beforehand.Nonvolatile compounds are salted out on the electrode 21b. Volatilesample molecules are vaporized and introduced into the ionizationportion 6 via the heated metallic block 4b. To increase the arrivalefficiency of sample molecules to the ionization portion 6, it ispossible to install a gas feed port 26 and flow a gas 20 such as drynitrogen gas toward the ionization portion 6. It is desirable to heatthe gas 20 beforehand. It is possible that by installing an exhaust port27 and exhausting gas outside from the exhaust port, a gas flow isgenerated toward the ionization portion 6 from the portion where thesolution is sprayed and sample molecules are introduced efficiently intothe ionization portion 6.

In FIG. 6, the electrospray method is described as a method for sprayinga solution. However, to change the spray direction of a sample solutionto a direction different from the arrangement direction of the ionintroduction aperture, it is possible to use a spray method other thanelectrospray, for example, heating spray or ultrasonic spray. When asubstance to be analyzed is volatile, it is heated, vaporized, anddiffused on the electrode 21b and reaches the ionization portion 6.

In an apparatus having the constitution shown in FIG. 6, nonvolatilecompounds salt out on the electrode 21b. Therefore, by removing andcleaning only this electrode 21b, it can be maintained easily. FIG. 7 isa drawing showing a constitution in which a solution is sprayed toward amess 23b in place of the opposite electrode 21b shown in FIG. 6. It isdesirable to heat the mesh 23b beforehand. A pan 28 can be installedbehind the mesh 23b and maintained simply by exchanging. Furthermore, asolution collected in the pan 28 is sampled and an analytical meansother than the mass spectrometry, for example, an analytical methodusing fluorescence or emission or an immunological analytical method maybe executed for it.

The present invention is characterized in that nonvolatile compounds ina solution are ionized by the first ionization means and then removed bythe electric field and a substance to be analyzed which is not ionizedby the first ionization means is ionized by the second ionization meansand analyzed. Therefore, if nonvolatile compounds can be ionized, thefirst ionization means may not be the electrospray method. FIG. 8 showsan embodiment in which the gas spray ionization method is used as afirst ionization means.

A sample solution is introduced into a capillary 61 via the pipe 1 andthe connector 2. The capillary 61 may be a metallic tube or aninsulating tube. A spray gas introduction tube 62 is arranged around thecapillary 61 and the spray gas 17 flows in it. When the spray gas 17increases its speed, the solution is crushed to pieces and fine dropletsare generated. In the droplets obtained by doing this, nonvolatilecompounds which exist in the solution as ions are fetched. When thesolvent is evaporated from the droplets, gaseous ions of the nonvolatilecompounds are generated. The trajectory of the gaseous ions is curved bythe potential applied to the needle electrode 7 installed in theionization portion 6, so that the ions cannot reach the ion introductionaperture 9a. As a result, the nonvolatile compounds do not salt out inthe neighborhood of the ion introduction aperture 9a and the ionintroduction aperture 9a is not clogged up. A substance to be analyzedwhich is electrically neutral reaches the ionization portion 6 bydiffusion in the same way as with the embodiment shown in FIG. 2 and isionized and analyzed. To promote vaporization of droplets, thevaporization portion 5 comprising the heated metallic block 4b may beinstalled. Droplets are vaporized by heat while they are passing throughthe aperture of the metallic block 4b. To increase the efficiency forremoving ions of nonvolatile compounds, it is possible to generate anelectric field between the spray gas introduction tube 62 and themetallic block 4b by the high voltage source 8c. Ions of nonvolatilecompounds are drifted by the electric field in the direction of themetallic block 4b or the spray gas introduction tube 62 according to theion polarity and captured by the metallic block 4b or the spray gasintroduction tube 62.

As shown by the above description, according to the present invention,even if a solution containing nonvolatile compounds of highconcentration is introduced into the ion source, the capillary forspraying the solution and the aperture for fetching ions generated underthe atmospheric pressure into a vacuum can be prevented from cloggingup. As a result, a substance to be analyzed in the solution can beionized stably for many hours and the ions can be introduced andanalyzed in the spectrometric portion arranged in a vacuum. Therefore, asample obtained from a living matter or environment can be analyzedwithout a complicated pretreatment being executed. Furthermore, a mobilephase containing a nonvolatile salt which cannot be used for many hoursin a conventional LC/MS can be used, so that analysis by the LC/MS fullyutilizing the separation ability of the LC is possible.

Main symbols used in the drawings mentioned above are shown below in abatch. 1: Pipe, 2: Connector, 3: Metallic tube, 4a, 4b: Metallic blocks,5: Vaporization portion, 6: Ionization portion, 7: Needle electrode, 8a,8b, 8c: High voltage sources, 9a, 9b: Ion introduction apertures: 10a,10b: Exhaust systems, 11: Differential pumping portion, 12: High vacuumportion, 13: Mass spectrometric portion, 14: Liquid chromatograph, 15:Electrospray portion, 16: Splitter, 17: Spray gas, 18: Auxiliary spraysolution, 19: Insulating tube, 20: Gas, 21a, 21b, 21c: Electrodes, 22a,22b: Heaters, 23a, 23b: Meshes, 24: Power source, 25: Glass tube, 26:Gas feed port, 27: Exhaust port, 28: Pan, 30: Power source, 31:Deflection electrode, 32: Capture plate, 40: Spray gas outlet, 41:Shielding plate, 50: Mobile phase reservoir, 51: Pump, 52: Sampleintroduction portion, 53: Separation column, 60: Gas spray iongeneration port, 61: Capillary, 62: Spray gas introduction tube.

What is claimed is:
 1. A mass spectrometric apparatuscomprising:supplying means for supplying a sample solution to an outlet;first ionization means for receiving the sample solution from the outletand electrospraying the received sample solution, thereby ionizing atleast a portion of the received sample solution; second ionization meanslocated at atmospheric pressure or substantially atmospheric pressurefor receiving at least a portion of the electrosprayed sample solutionproduced by the first ionization means and ionizing at least a portionof the received electrosprayed sample solution, thereby producing ions;and analyzing means for receiving at least some of the ions produced bythe second ionization means and analyzing masses of the received ions.2. A mass spectrometric apparatus according to claim 1, wherein theelectrosprayed sample solution produced by the first ionization meansincludes droplets; andwherein the mass spectrometric apparatus furthercomprises vaporization means disposed between the first ionization meansand the second ionization means for vaporizing the droplets in theelectrosprayed sample solution produced by the first ionization meansbefore the electrosprayed sample solution produced by the firstionization means is received by the second ionization means.
 3. A massspectrometric apparatus according to claim 1, wherein the secondionization means chemically ionizes the received electrosprayed samplesolution by causing the received electrosprayed sample solution toundergo a chemical reaction at atmospheric pressure or substantiallyatmospheric pressure.
 4. A mass spectrometer apparatus according toclaim 1, wherein the sample solution includes a solvent and a solute,the first ionization means is located at atmospheric pressure orsubstantially atmospheric pressure, and the analyzing means includes ananalyzing chamber being an aperture for receiving at least some of theions, the analyzing chamber analyzing masses of the received ions.
 5. Amass spectrometer apparatus according to claim 4, wherein the secondionization means chemically ionizes the received electrosprayed samplesolution by causing the received electrosprayed sample solution toundergo a chemical reaction.
 6. A mass spectrometer apparatus accordingto claim 4, wherein the second ionization means comprises a needleelectrode for producing corona discharge.
 7. A mass spectrometerapparatus according to claim 4, wherein the second ionization meanscomprises an electrode for generating an electric field to eliminate atleast a portion of the ions produced by the first ionization means.
 8. Amass spectrometric apparatus comprising:supplying means for supplying asample solution to an outlet; first ionization means for receiving thesample solution from the outlet and gas-spraying the received samplesolution, thereby ionizing at least a portion of the received samplesolution; second ionization means located at atmospheric pressure orsubstantially atmospheric pressure for receiving at least a portion ofthe gas-sprayed sample solution produced by the first ionization meansand ionizing at least a portion of the received gas-sprayed samplesolution, thereby producing ions; and analyzing means for receiving atleast some of the ions produced by the second ionization means andanalyzing masses of the received ions.
 9. A mass spectrometric apparatusaccording to claim 8, wherein the gas-sprayed sample solution producedby the first ionization means includes droplets; andwherein the massspectrometric apparatus further comprises vaporization means disposedbetween the first ionization means and the second ionization means forvaporizing the droplets in the gas-sprayed sample solution produced bythe first ionization means before the gas-sprayed sample solutionproduced by the first ionization means is received by the secondionization means.
 10. A mass spectrometric apparatus according to claim8, wherein the second ionization means chemically ionizes the receivedgas-sprayed sample solution by causing the received gas-sprayed samplesolution to undergo a chemical reaction at atmospheric pressure orsubstantially atmospheric pressure.
 11. A mass spectrometer apparatusaccording to claim 8, wherein the sample solution includes a solvent anda solute, the first ionization means is located at atmospheric pressureor substantially atmospheric pressure, and the analyzing means includesan analyzing chamber being an aperture for receiving at least some ofthe ions, the analyzing chamber analyzing masses of the received ions.12. A mass spectrometer apparatus according to claim 11, wherein thesecond ionization means chemically ionizes the received gas-sprayedsample solution by causing the received gas-sprayed sample solution toundergo a chemical reaction.
 13. A mass spectrometer apparatus accordingto claim 11, wherein the second ionization means comprises a needleelectrode for producing corona discharge.
 14. A mass spectrometerapparatus according to claim 11, wherein the second ionization meanscomprises an electrode for generating an electric field to eliminate atleast a portion of the ions produced by the first ionization means. 15.A mass spectrometric apparatus comprising:supplying means for supplyinga sample solution to an outlet at a predetermined flow rate; firstionization means for receiving the sample solution from the outlet andelectrospraying the received sample solution, thereby ionizing at leasta portion of the received sample solution; second ionization meanslocated at atmospheric pressure or substantially atmospheric pressurefor receiving at least a portion of the electrosprayed sample solutionproduced by the first ionization means and ionizing at least a portionof the received electrosprayed sample solution, thereby producing ions;and analyzing means for receiving at least some of the ions produced bythe second ionization means and analyzing masses of the received ions.16. A mass spectrometric apparatus according to claim 15, wherein thesupplying means includes separation means for separating the samplesolution into components.
 17. A mass spectrometric apparatus accordingto claim 15, wherein the electrosprayed sample solution produced by thefirst ionization means includes droplets; andwherein the massspectrometric apparatus further comprises vaporization means disposedbetween the first ionization means and the second ionization means forvaporizing the droplets in the electrosprayed sample solution producedby the first ionization means before the electrosprayed sample solutionproduced by the first ionization means is received by the secondionization means.
 18. A mass spectrometric apparatus according to claim15, wherein the second ionization means chemically ionizes the receivedelectrosprayed sample solution by causing the received electrosprayedsample solution to undergo a chemical reaction at atmospheric pressureor substantially atmospheric pressure.
 19. A mass spectrometricapparatus comprising:supplying means for supplying a sample solution toan outlet at a predetermined flow rate; first ionization means forreceiving the sample solution from the outlet and gas-spraying thereceived sample solution, thereby ionizing at least a portion of thereceived sample solution; second ionization means located at atmosphericpressure or substantially atmospheric pressure for receiving at least aportion of the gas-sprayed sample solution produced by the firstionization means and ionizing at least a portion of the receivedgas-sprayed sample solution, thereby producing ions; and analyzing meansfor receiving at least some of the ions produced by the secondionization means and analyzing masses of the received ions.
 20. A massspectrometric apparatus according to claim 19, wherein the supplyingmeans includes separation means for separating the sample solution intocomponents.
 21. A mass spectrometric apparatus according to claim 19,wherein the gas-sprayed sample solution produced by the first ionizationmeans includes droplets; andwherein the mass spectrometric apparatusfurther comprises vaporization means disposed between the firstionization means and the second ionization means for vaporizing thedroplets in the gas-sprayed sample solution produced by the firstionization means before the gas-sprayed sample solution produced by thefirst ionization means is received by the second ionization means.
 22. Amass spectrometric apparatus according to claim 19, wherein the secondionization means chemically ionizes the received gas-sprayed samplesolution by causing the received gas-sprayed sample solution to undergoa chemical reaction at atmospheric pressure or substantially atmosphericpressure.
 23. A mass spectrometric apparatus comprising:supplying meansfor supplying a sample solution to an outlet, the sample solutionincluding a solvent and a solute; first ionization means for receivingthe sample solution from the outlet and electrospraying the receivedsample solution, thereby ionizing at least a portion of the receivedsample solution; second ionization means located at atmospheric pressureor substantially atmospheric pressure for receiving at least a portionof the electrosprayed sample solution produced by the first ionizationmeans and ionizing at least a portion of the received electrosprayedsample solution, thereby producing ions; and mass spectrometric meansfor receiving at least some of the ions produced by the secondionization means and analyzing masses of the received ions.
 24. A massspectrometric apparatus according to claim 23, wherein theelectrosprayed sample solution produced by the first ionization meansincludes droplets; andwherein the mass spectrometric apparatus furthercomprises vaporization means disposed between the first ionization meansand the second ionization means for vaporizing the droplets in theelectrosprayed sample solution produced by the first ionization meansbefore the electrosprayed sample solution produced by the firstionization means is received by the second ionization means.
 25. A massspectrometric apparatus according to claim 23, wherein the secondionization means chemically ionizes the received electrosprayed samplesolution by causing the received electrosprayed sample solution toundergo a chemical reaction at atmospheric pressure or substantiallyatmospheric pressure.
 26. A mass spectrometric apparatuscomprising:supplying means for supplying a sample solution to an outlet,the sample solution including a solvent and a solute; first ionizationmeans for receiving the sample solution from the outlet and gas-sprayingthe received sample solution, thereby ionizing at least a portion of thereceived sample solution; second ionization means located at atmosphericpressure or substantially atmospheric pressure for receiving at least aportion of the gas-sprayed sample solution produced by the firstionization means and ionizing at least a portion of the receivedgas-sprayed sample solution, thereby producing ions; and massspectrometric means for receiving at least some of the ions produced bythe second ionization means and analyzing masses of the received ions.27. A mass spectrometric apparatus according to claim 26, wherein thegas-sprayed sample solution produced by the first ionization meansincludes droplets; andwherein the mass spectrometric apparatus furthercomprises vaporization means disposed between the first ionization meansand the second ionization means for vaporizing the droplets in thegas-sprayed sample solution produced by the first ionization meansbefore the gas-sprayed sample solution produced by the first ionizationmeans is received by the second ionization means.
 28. A massspectrometric apparatus according to claim 26, wherein the secondionization means chemically ionizes the received gas-sprayed samplesolution by causing the received gas-sprayed sample solution to undergoa chemical reaction at atmospheric pressure or substantially atmosphericpressure.
 29. A mass spectrometric apparatus comprising:supplying meansfor supplying a sample solution to an outlet at a predetermined flowrate, the sample solution including a solvent and a solute; firstionization means for receiving the sample solution from the outlet andelectrospraying the received sample solution, thereby ionizing at leasta portion of the received sample solution; second ionization meanslocated at atmospheric pressure or substantially atmospheric pressurefor receiving at least a portion of the electrosprayed sample solutionproduced by the first ionization means and ionizing at least a portionof the received electrosprayed sample solution, thereby producing ions;and mass spectrometric means for receiving at least some of the ionsproduced by the second ionization means and analyzing masses of thereceived ions.
 30. A mass spectrometric apparatus according to claim 29,wherein the supplying means includes separation means for separating thesample solution into components.
 31. A mass spectrometric apparatusaccording to claim 29, wherein the electrosprayed sample solutionproduced by the first ionization means includes droplets; andwherein themass spectrometric apparatus further comprises vaporization meansdisposed between the first ionization means and the second ionizationmeans for vaporizing the droplets in the electrosprayed sample solutionproduced by the first ionization means before the electrosprayed samplesolution produced by the first ionization means is received by thesecond ionization means.
 32. A mass spectrometric apparatus according toclaim 29, wherein the second ionization means chemically ionizes thereceived electrosprayed sample solution by causing the receivedelectrosprayed sample solution to undergo a chemical reaction atatmospheric pressure or substantially atmospheric pressure.
 33. A massspectrometric apparatus comprising:supplying means for supplying asample solution to an outlet at a predetermined flow rate, the samplesolution including a solvent and a solute; first ionization means forreceiving the sample solution from the outlet and gas-spraying thereceived sample solution, thereby ionizing at least a portion of thereceived sample solution; second ionization means located at atmosphericpressure or substantially atmospheric pressure for receiving at least aportion of the gas-sprayed sample solution produced by the firstionization means and ionizing at least a portion of the receivedgas-sprayed sample solution, thereby producing ions; and massspectrometric means for receiving at least some of the ions produced bythe second ionization means and analyzing masses of the received ions.34. A mass spectrometric apparatus according to claim 33, wherein thesupplying means includes separation means for separating the samplesolution into components.
 35. A mass spectrometric apparatus accordingto claim 33, wherein the gas-sprayed sample solution produced by thefirst ionization means includes droplets; andwherein the massspectrometric apparatus further comprises vaporization means disposedbetween the first ionization means and the second ionization means forvaporizing the droplets in the gas-sprayed sample solution produced bythe first ionization means before the gas-sprayed sample solutionproduced by the first ionization means is received by the secondionization means.
 36. A mass spectrometric apparatus according to claim33, wherein the second ionization means chemically ionizes the receivedgas-sprayed sample solution by causing the received gas-sprayed samplesolution to undergo a chemical reaction at atmospheric pressure orsubstantially atmospheric pressure.
 37. An analytical method comprisingthe steps of:preparing a sample solution including a solvent and asolute; separating the sample solution into components; electrosprayingthe separated sample solution at atmospheric pressure or substantiallyatmospheric pressure, thereby firstly ionizing at least a portion of theseparated sample solution; secondly ionizing at least a portion of theelectrosprayed separated sample solution at atmospheric pressure orsubstantially atmospheric pressure, thereby producing ions; andreceiving through an aperture of an analyzing chamber at least some ofthe ions produced in the first and second ionizations and analyzingmasses of the received ions within the analyzing chamber.
 38. Ananalytical method comprising the steps of:preparing a sample solutionincluding a solvent and a solute; separating the sample solution intocomponents; gas-spraying the separated sample solution at atmosphericpressure or substantially atmospheric pressure, thereby firstly ionizingat least a portion of the separated sample solution; secondly ionizingat least a portion of the gas-sprayed separated sample solution atatmospheric pressure or substantially atmospheric pressure, therebyproducing ions; and receiving through an aperture of an analyzingchamber at least some of the ions produced in the first and secondionizations and analyzing masses of the received ions within theanalyzing chamber.
 39. A mass spectrometric apparatus comprising:asupplier which supplies a sample solution to an outlet; a first ionizerwhich receives the sample solution from the outlet and electrosprays thereceived sample solution, thereby ionizing at least a portion of thereceived sample solution; a second ionizer located at atmosphericpressure or substantially atmospheric pressure which receives at least aportion of the electrosprayed sample solution produced by the firstionizer and ionizes at least a portion of the received electrosprayedsample solution, thereby producing ions; and an analyzer which receivesat least some of the ions produced by the second ionizer and analyzesmasses of the received ions.
 40. A mass spectrometer apparatus accordingto claim 39, wherein the sample solution includes a solvent and asolute, the first ionizer is located at atmospheric pressure orsubstantially atmospheric pressure, and the analyzer includes ananalyzing chamber being an aperture for receiving at least some of theions, the analyzing chamber analyzing masses of the received ions.
 41. Amass spectrometer apparatus according to claim 40, wherein the secondionizer chemically ionizes the received electrosprayed sample solutionby causing the received electrosprayed sample solution to undergo achemical reaction.
 42. A mass spectrometer apparatus according to claim40, wherein the second ionizer comprises a needle electrode forproducing corona discharge.
 43. A mass spectrometer apparatus accordingto claim 40, wherein the second ionizer comprises an electrode forgenerating an electric field to eliminate at least a portion of the ionsproduced by the first ionizer.
 44. A mass spectrometric apparatusaccording to claim 39, wherein the electrosprayed sample solutionproduced by the first ionizer includes droplets; andwherein the massspectrometric apparatus further comprises a vaporizer disposed betweenthe first ionizer and the second ionizer which vaporizes the droplets inthe electrosprayed sample solution produced by the first ionizer beforethe electrosprayed sample solution produced by the first ionizer isreceived by the second ionizer.
 45. A mass spectrometric apparatusaccording to claim 39, wherein the second ionizer chemically ionizes thereceived electrosprayed sample solution by causing the receivedelectrosprayed sample solution to undergo a chemical reaction atatmospheric pressure or substantially atmospheric pressure.
 46. A massspectrometric apparatus comprising:a supplier which supplies a samplesolution to an outlet; a first ionizer which receives the samplesolution from the outlet and gas-sprays the received sample solution,thereby ionizing at least a portion of the received sample solution; asecond ionizer located at atmospheric pressure or substantiallyatmospheric pressure which receives at least a portion of thegas-sprayed sample solution produced by the first ionizer and ionizes atleast a portion of the received gas-sprayed sample solution, therebyproducing ions; and an analyzer which receives at least some of the ionsproduced by the second ionizer and analyzes masses of the received ions.47. A mass spectrometer apparatus according to claim 46, wherein thesample solution includes a solvent and a solute, the first ionizer islocated at atmospheric pressure or substantially atmospheric pressure,and the analyzer includes an analyzing chamber being an aperture forreceiving at least some of the ions, the analyzing chamber analyzingmasses of the received ions.
 48. A mass spectrometer apparatus accordingto claim 47, wherein the second ionizer chemically ionizes the receivedgas-sprayed sample solution by causing the received gas-sprayed samplesolution to undergo a chemical reaction.
 49. A mass spectrometerapparatus according to claim 47, wherein the second ionizer comprises aneedle electrode for producing corona discharge.
 50. A mass spectrometerapparatus according to claim 47, wherein the second ionizer comprises anelectrode for generating an electric field to eliminate at least aportion of the ions produced by the first ionizer.
 51. A massspectrometric apparatus according to claim 46, wherein the gas-sprayedsample solution produced by the first ionizer includes droplets;andwherein the mass spectrometric apparatus further comprises avaporizer disposed between the first ionizer and the second ionizerwhich vaporizes the droplets in the gas-sprayed sample solution producedby the first ionizer before the gas-sprayed sample solution produced bythe first ionizer is received by the second ionizer.
 52. A massspectrometric apparatus according to claim 46, wherein the secondionizer chemically ionizes the received gas-sprayed sample solution bycausing the received gas-sprayed sample solution to undergo a chemicalreaction at atmospheric pressure or substantially atmospheric pressure.53. A mass spectrometric apparatus comprising:a supplier which suppliesa sample solution to an outlet at a predetermined flow rate; a firstionizer which receives the sample solution from the outlet andelectrosprays the received sample solution, thereby ionizing at least aportion of the received sample solution; a second ionizer located atatmospheric pressure or substantially atmospheric pressure whichreceives at least a portion of the electrosprayed sample solutionproduced by the first ionizer and ionizes at least a portion of thereceived electrosprayed sample solution, thereby producing ions; and ananalyzer which receives at least some of the ions produced by the secondionizer and analyzes masses of the received ions.
 54. A massspectrometric apparatus according to claim 53, wherein the supplierincludes a separator which separates the sample solution intocomponents.
 55. A mass spectrometric apparatus according to claim 53,wherein the electrosprayed sample solution produced by the first ionizerincludes droplets; andwherein the mass spectrometric apparatus furthercomprises a vaporizer disposed between the first ionizer and the secondionizer which vaporizes the droplets in the electrosprayed samplesolution produced by the first ionizer before the electrosprayed samplesolution produced by the first ionizer is received by the secondionizer.
 56. A mass spectrometric apparatus according to claim 53,wherein the second ionizer chemically ionizes the receivedelectrosprayed sample solution by causing the received electrosprayedsample solution to undergo a chemical reaction at atmospheric pressureor substantially atmospheric pressure.
 57. A mass spectrometricapparatus comprising:a supplier which supplies a sample solution to anoutlet at a predetermined flow rate; a first ionizer which receives thesample solution from the outlet and gas-sprays the received samplesolution, thereby ionizing at least a portion of the received samplesolution; a second ionizer located at atmospheric pressure orsubstantially atmospheric pressure for receiving at least a portion ofthe gas-sprayed sample solution produced by the first ionizer andionizes at least a portion of the received gas-sprayed sample solution,thereby producing ions; and an analyzer which receives at least some ofthe ions produced by the second ionizer and analyzes masses of thereceived ions.
 58. A mass spectrometric apparatus according to claim 57,wherein the supplier includes a separator which separates the samplesolution into components.
 59. A mass spectrometric apparatus accordingto claim 57, wherein the gas-sprayed sample solution produced by thefirst ionizer includes droplets; andwherein the mass spectrometricapparatus further comprises a vaporizer disposed between the firstionizer and the second ionizer which vaporizes the droplets in thegas-sprayed sample solution produced by the first ionizer before thegas-sprayed sample solution produced by the first ionizer is received bythe second ionizer.
 60. A mass spectrometric apparatus according toclaim 57, wherein the second ionizer chemically ionizes the receivedgas-sprayed sample solution by causing the received gas-sprayed samplesolution to undergo a chemical reaction at atmospheric pressure orsubstantially atmospheric pressure.
 61. A mass spectrometric apparatuscomprising:a supplier which supplies a sample solution to an outlet, thesample solution including a solvent and a solute; a first ionizer whichreceives the sample solution from the outlet and electrosprays thereceived sample solution, thereby ionizing at least a portion of thereceived sample solution; a second ionizer located at atmosphericpressure or substantially atmospheric pressure which receives at least aportion of the electrosprayed sample solution produced by the firstionizer and ionizes at least a portion of the received electrosprayedsample solution, thereby producing ions; and a mass spectrometer whichreceives at least some of the ions produced by the second ionizer andanalyzes masses of the received ions.
 62. A mass spectrometric apparatusaccording to claim 61, wherein the electrosprayed sample solutionproduced by the first ionizer includes droplets; andwherein the massspectrometric apparatus further comprises a vaporizer disposed betweenthe first ionizer and the second ionizer which vaporizes the droplets inthe electrosprayed sample solution produced by the first ionizer beforethe electrosprayed sample solution produced by the first ionizer isreceived by the second ionizer.
 63. A mass spectrometric apparatusaccording to claim 61, wherein the second ionizer chemically ionizes thereceived electrosprayed sample solution by causing the receivedelectrosprayed sample solution to undergo a chemical reaction atatmospheric pressure or substantially atmospheric pressure.
 64. A massspectrometric apparatus comprising:a supplier which supplies a samplesolution to an outlet, the sample solution including a solvent and asolute; a first ionizer which receives the sample solution from theoutlet and gas-sprays the received sample solution, thereby ionizing atleast a portion of the received sample solution; a second ionizerlocated at atmospheric pressure or substantially atmospheric pressurewhich receives at least a portion of the gas-sprayed sample solutionproduced by the first ionizer and ionizes at least a portion of thereceived gas-sprayed sample solution, thereby producing ions; and a massspectrometer which receives at least some of the ions produced by thesecond ionizer and analyzes masses of the received ions.
 65. A massspectrometric apparatus according to claim 64, wherein the gas-sprayedsample solution produced by the first ionizer includes droplets;andwherein the mass spectrometric apparatus further comprises avaporizer disposed between the first ionizer and the second ionizerwhich vaporizes the droplets in the gas-sprayed sample solution producedby the first ionizer before the gas-sprayed sample solution produced bythe first ionizer is received by the second ionizer.
 66. A massspectrometric apparatus according to claim 64, wherein the secondionizer chemically ionizes the received gas-sprayed sample solution bycausing the received gas-sprayed sample solution to undergo a chemicalreaction at atmospheric pressure or substantially atmospheric pressure.67. A mass spectrometric apparatus comprising:a supplier which suppliesa sample solution to an outlet at a predetermined flow rate, the samplesolution including a solvent and a solute; a first ionizer whichreceives the sample solution from the outlet and electrosprays thereceived sample solution, thereby ionizing at least a portion of thereceived sample solution; a second ionizer located at atmosphericpressure or substantially atmospheric pressure which receives at least aportion of the electrosprayed sample solution produced by the firstionizer and ionizes at least a portion of the received electrosprayedsample solution, thereby producing ions; and a mass spectrometer whichreceives at least some of the ions produced by the second ionizer andanalyzes masses of the received ions.
 68. A mass spectrometric apparatusaccording to claim 67, wherein the supplier includes a separator whichseparates the sample solution into components.
 69. A mass spectrometricapparatus according to claim 67, wherein the electrosprayed samplesolution produced by the first ionizer includes droplets; andwherein themass spectrometric apparatus further comprises a vaporizer disposedbetween the first ionizer and the second ionizer which vaporizes thedroplets in the electrosprayed sample solution produced by the firstionizer before the electrosprayed sample solution produced by the firstionizer is received by the second ionizer.
 70. A mass spectrometricapparatus according to claim 67, wherein the second ionizer chemicallyionizes the received electrosprayed sample solution by causing thereceived electrosprayed sample solution to undergo a chemical reactionat atmospheric pressure or substantially atmospheric pressure.
 71. Amass spectrometric apparatus comprising:a supplier which supplies asample solution to an outlet at a predetermined flow rate, the samplesolution including a solvent and a solute; a first ionizer whichreceives the sample solution from the outlet and gas-sprays the receivedsample solution, thereby ionizing at least a portion of the receivedsample solution; a second ionizer located at atmospheric pressure orsubstantially atmospheric pressure which receives at least a portion ofthe gas-sprayed sample solution produced by the first ionizer andionizes at least a portion of the received gas-sprayed sample solution,thereby producing ions; and a mass spectrometer which receives at leastsome of the ions produced by the second ionizer and analyzes masses ofthe received ions.
 72. A mass spectrometric apparatus according to claim71, wherein the supplier includes a separator which separates the samplesolution into components.
 73. A mass spectrometric apparatus accordingto claim 71, wherein the gas-sprayed sample solution produced by thefirst ionizer includes droplets; andwherein the mass spectrometricapparatus further comprises a vaporizer disposed between the firstionizer and the second ionizer which vaporizes the droplets in thegas-sprayed sample solution produced by the first ionizer before thegas-sprayed sample solution produced by the first ionizer is received bythe second ionizer.
 74. A mass spectrometric apparatus according toclaim 71, wherein the second ionizer chemically ionizes the receivedgas-sprayed sample solution by causing the received gas-sprayed samplesolution to undergo a chemical reaction at atmospheric pressure orsubstantially atmospheric pressure.
 75. A mass spectrometric apparatuscomprising:a supplier which supplies a sample solution to an outlet; afirst ionizer which receives the sample solution from the outlet andelectrosprays the received sample solution, thereby ionizing at least aportion of the received sample solution; a second ionizer which receivesat least a portion of the electrosprayed sample solution produced by thefirst ionizer and ionizes at least a portion of the receivedelectrosprayed sample solution, thereby producing ions; and an analyzerlocated at a low pressure region which receives at least some of theions produced by the second ionizer and analyzes masses of the receivedions; wherein the first ionizer and the second ionizer are located at aregion which has higher pressure than the low pressure region.
 76. Amass spectrometric apparatus according to claim 75, wherein the samplesolution includes a solvent and a solute, and the analyzer includes ananalyzing chamber having an aperture for receiving at least some of theions, the analyzing chamber analyzing masses of the received ions.
 77. Amass spectrometric apparatus according to claim 76, wherein the secondionizer chemically ionizes the received electrosprayed sample solutionby causing the received electrosprayed sample solution to undergo achemical reactions.
 78. A mass spectrometric apparatus according toclaim 76, wherein the second ionizer comprises a needle electrode forproducing corona discharge.
 79. A mass spectrometric apparatus accordingto claim 76, wherein the second ionize comprises an electrode forgenerating an electric field to eliminate at least a portion of ionsproduced by the first ionizer.
 80. A mass spectrometric apparatusaccording to claim 75, wherein the electrosprayed sample solutionproduced by the first ionizer includes droplets, and wherein the massspectrometric apparatus further comprises a vaporizer disposed betweenthe first ionizer and the second ionizer which vaporizes the droplets inthe electrosprayed sample solution produced by the first ionizer beforethe electrosprayed sample solution produced by the first ionizer isreceived by the second ionizer.
 81. A mass spectrometric apparatusaccording to claim 75, wherein the second ionizer chemically ionizes thereceived electrosprayed sample solution by causing the receivedelectrosprayed sample solution to undergo a chemical reaction.
 82. Amass spectrometric apparatus comprising:a supplier which supplies asample solution to an outlet; a first ionizer which receives the samplesolution from the outlet and gas-sprays the received sample solution,thereby ionizing at least a portion of the received sample solution; asecond ionizer which receives at least a portion of the gas-sprayedsample solution produced by the first ionizer and ionizes at least aportion of the received gas-sprayed sample solution, thereby producingions; and an analyzer located at a low pressure region which receives atleast some of the ions produced by the second ionizer and analyzesmasses of the received ions; wherein the first ionizer and the secondionizer are located at a region which has higher pressure than the lowpressure region.
 83. A mass spectrometric apparatus according to claim82, wherein the sample solution includes a solvent and a solute, and theanalyzer includes an analyzing chamber having an aperture for receivingat least some of the ions, the analyzing chamber analyzing asses of thereceived ions.
 84. A mass spectrometric apparatus according to claim 83,wherein the second ionizer chemically ionizes the gas-sprayed samplesolution by causing the received gas-sprayed sample solution to undergoa chemical reaction.
 85. A mass spectrometric apparatus according toclaim 83, wherein the second ionizer comprises a needle electrode forproducing corona discharge.
 86. A mass spectrometric apparatus accordingto claim 83, wherein the second ionizer comprises an electrodeforgenerating an electric field to eliminate at least a portion of ionsproduced by the first ionizer.
 87. A mass spectrometric apparatusaccording to claim 82, wherein the gas-sprayed sample solution producedby the first ionizer includes droplets, and wherein the massspectrometric apparatus further comprises a vaporizer disposed betweenthe first ionizer and the second ionizer which vaporizes the droplets inthe gas-sprayed sample solution produced by the first ionizer before thegas-sprayed sample solution produced by the first ionizer is received bythe second ionizer.
 88. A mass spectrometric apparatus according toclaim 82, wherein the second ionizer chemically ionizes the receivedgas-sprayed sample solution by causing the received gas-sprayed samplesolution to undergo a chemical reaction.
 89. A mass spectrometricapparatus comprising:a supplier which supplies sample solution; anelectrospray ion source which ionizes the sample solution; a chemicalionization ion source which ionizes the sample solution; and an analyzerlocated at a low pressure region which analyzes masses of the ions;wherein the electrospray ion source and the chemical ionization ionsource are located at a region which has higher pressure than the lowpressure region.
 90. A mass spectrometric apparatus according to claim89, wherein the sample solution includes a solvent and a solute, and theanalyzer includes an analyzing chamber having an aperture for receivingaq least some of the ions, the analyzing chamber analyzing masses of thereceived ions.
 91. A mass spectrometric apparatus according to claim 89,wherein the chemical ionization ion source comprises a needle electrodefor producing corona discharge.
 92. A mass spectrometric apparatuscomprising:a supplier which supplies a sample solution; an gas-spray ionsource which ionizes at least a portion of the sample solution; achemical ionization ion source which ionizes the sample solution; and ananalyzer located at a low pressure region which receives at least someof the ions produced by the ions sources and analyzes masses of thereceived ions; wherein the gas-spray ion source and the chemicalionization ion source are located at a region which has higher pressurethan the low pressure region.
 93. A mass spectrometric apparatusaccording to claim 92, wherein the sample solution includes a solventand a solute, and the analyzer includes an analyzing chamber having anaperture for receiving at least some of the ions, the analyzing chamberanalyzing masses of the received ions.
 94. A mass spectrometricapparatus according to claim 92, wherein the chemical ionization ionsource comprises a needle electrode for producing corona discharge. 95.A mass spectrometric apparatus comprising:a supplier which supplies asample solution; and an analyzer located at a low pressure region whichanalyzes masses of ions produced from the sample solution; whereinplural on sources are located at a region which has higher pressure thanthe low pressure region to ionize at least a portion of the samplesolution.
 96. A mass spectrometric apparatus according to claim 95,wherein one of the plural ion sources is an electrospray ion source. 97.A mass spectrometric apparatus according to claim 95, wherein one of theplural ion sources is a chemical ionization ion source.
 98. A massspectrometric apparatus according to claim 95, wherein one of the pluralion sources is a gas-spray ion source.
 99. An ion source comprising:afirst ionizer which ionizes a solution by electrospray; and a secondionizer which ionizes a solution by chemical reaction.
 100. An ionsource according to claim 99, wherein the second ionizer comprises aneedle electrode for producing corona discharge.
 101. An ion sourcecomprising:a first ionizer which ionizes a solution by gas-spray; and asecond ionizer which ionizes a solution by chemical reaction.
 102. Anion source according to claim 101, wherein the second ionizer comprisesa needle electrode for producing discharge.